Sp1 is involved in regulation of cystathionine 纬-lyase gene expression and biological function by PI3K/Akt pathway in human hepatocellular carcinoma cell lines

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• 作者：Peng Yin^a ; Chao Zhao^a ; Zengxia Li^a ; ^b ; ^c ; Chuanzhong Mei^a ; Wantong Yao^a ; Yonglei Liu^a ; Na Li^a ; Jingjing Qi^a ; Liying Wang^a ; ^b ; ^c ; Yinghong Shi^d ; Shuangjian Qiu^d ; Jia Fan^d ; Xiliang Zha^a ; ^b ; ^c ; ^{xlzha@shmu.edu.cn}
• 关键词：CSE ; cystathionine 纬-lyase ; PLP ; pyridoxal-5&prime ; -phosphate ; PI3K ; phosphoinositide 3-kinase ; Myr-Akt2 ; myristylated variants of Akt2 ; IGF-1 ; insulin-like growth factor-1 ; PTEN ; phosphatase and tensing homolog ; CHX ; cycloheximide ; MEF ; mouse embryonic
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：June, 2012
• 卷：24
• 期：6
• 页码：1229-1240
• 文件大小：1649 K

摘要

Hydrogen sulfide (H₂S) has been found to play an important role as a novel gasotransmitter involved in many biological processes. The regulatory role of endogenous H₂S-producing enzyme on cancer cell survival is complex and unclear. According to the data that cystathionine 纬-lyase (CSE) gene, catalyzed H₂S production in trans-sulfuration pathway, was upregulated in Akt stably transformed mouse embryonic fibroblast cells, the mechanisms that elevated CSE expression by PI3K/Akt signaling pathway and its biological functions in cell survival were studied. In the present study, firstly, the results showed that PI3K/Akt positively correlated with CSE expression levels in human hepatocellular carcinoma cell lines. CSE expression was decreased by the PI3K inhibitor or Akt deletion, while upregulated with the activating of Akt. Based on dual-luciferase reporter assay, the 鈭?#xA0;592/+139 gene fragment represented the CSE core promoter, and the PI3K/Akt pathway regulated CSE expression on transcriptional level. Sp1 was the critical transcription factor in regulation of CSE expression via the mutation of transcription factor binding sites on the promoter. Furthermore, we proved that Sp1 could directly bind to CSE promoter by ChIP assay. In addition, we explored that the endogenous H₂S production was connected with the regulated CSE expression, and CSE/H₂S promoted human hepatocellular carcinoma cell proliferation via cell cycle progression regulation. In summary, we have, for the first time, demonstrated that PI3K/Akt pathway regulates the CSE expression via Sp1, which is particularly important to understand the effect of PI3K/Akt and CSE on the tumorigenesis.